EP1339715A2 - Heterocyclic ether substituted imidazoquinolines - Google Patents

Heterocyclic ether substituted imidazoquinolines

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Publication number
EP1339715A2
EP1339715A2 EP01990852A EP01990852A EP1339715A2 EP 1339715 A2 EP1339715 A2 EP 1339715A2 EP 01990852 A EP01990852 A EP 01990852A EP 01990852 A EP01990852 A EP 01990852A EP 1339715 A2 EP1339715 A2 EP 1339715A2
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EP
European Patent Office
Prior art keywords
alkyl
imidazo
heteroaryl
amine
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP01990852A
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German (de)
English (en)
French (fr)
Inventor
Leslie J. Charles
Joseph F. Dellaria
George W. Griesgraber
Philip D. Heppner
Karl J. Manske
John W. Mickelson
Michael J. Rice
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3M Innovative Properties Co
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3M Innovative Properties Co
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Publication of EP1339715A2 publication Critical patent/EP1339715A2/en
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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Definitions

  • This invention relates to imidazoquinoline compounds that have ether and heterocycle or heteroaryl functionality at the 1 -position, and to pharmaceutical compositions containing such compounds.
  • a further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals, and in the treatment of diseases, including viral and neoplastic diseases.
  • this invention provides imidazo[4, 5-c]quinoline-4- amine and tetrahydroimidazo[4, 5-c]quinoline-4-amine compounds that have an ether containing substituent at the 1 -position.
  • the compounds are described by Formulas (I), (II), (III) and (IV), which are defined in more detail infra. These compounds share the general structural formula
  • the compounds of Formulas (I), (II), (III), and (IV) are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This makes the compounds useful in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
  • the invention further provides pharmaceutical compositions containing the immune response modifying compounds, and methods of inducing cytokine biosynthesis in an animal, treating a viral infection in an animal, and/or treating a neoplastic disease in an animal by administering a compound of Formula (I), (II), (III), or (IV) to the animal.
  • the invention provides methods of synthesizing the compounds of the invention and intermediates useful in the synthesis of these compounds.
  • Imidazoquinoline compounds of the invention which have ether and heterocyclyl or heteroaryl functionality at the 1 -position are represented by Formula (I):
  • X is -CHR 3 -, -CHR 3 -alkyl-, or -CHR 3 -alkenyl-;
  • Ri is selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • R- t is alkyl or alkenyl, which may be interrupted by one or more -0- groups; each R 3 is independently H or C ⁇ - ⁇ o alkyl; each Y is independently -O- or ⁇ S(O)o- 2 -; n is 0 to 4; and each R present is independently selected from the group consisting of Cj-io alkyl, C ⁇ - ⁇ o alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • the invention also provides imidazoquinoline compounds that contain ether functionality at the 1 -position, where the ether containing substituent also contains an alkynyl group and a heterocyclyl or heteroaryl group. These compounds are represented by Formula (II):
  • X is -CHR 3 -, -CHR 3 -alkyl-, or -CHR 3 -alkenyl-;
  • Rio is selected from the group consisting of heteroaryl and heterocyclyl
  • R 2 is selected from the group consisting of: -hydrogen; -alkyl; -alkenyl;
  • each R 3 is independently H or Ci-io alkyl; each Y is independently -O- or -S(O)o- 2 -; and each R present is independently selected from the group consisting of Ci-io alkyl, CM O alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • the invention also includes tetrahydroimidazoqumoline compounds that bear an ether and heterocyclyl or heteroaryl containing substituent at the 1 -position.
  • tetrahydroimidazoquinoline compounds are represented by Formula (III):
  • Ri is selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • Ri is alkyl or alkenyl, which may be interrupted by one or more -0- groups; each R 3 is independently H or Ci-io alkyl; each Y is independently -O- or -S(O)o- 2 -; n is 0 to 4; and each R present is independently selected from the group consisting of Ci-io alkyl, Ci-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • An additional class of immune response modifying compounds of the invention are tetrahydroimidazoquinoline compounds that have an ether containing substituent at the 1- position, where the ether containing substituent also contains an alkynyl group and a heterocyclyl or heteroaryl group. These compounds are represented by Formula (IV):
  • R 2 is selected from the group consisting of:
  • each R 3 is independently H or Ci-io alkyl; each Y is independently -O- or -S(O)o- 2 -; n is 0 to 4; and each R present is independently selected from the group consisting of Ci-io alkyl, Ci-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • R, R 2 , X and n are as defined above and Rn is alkyl substituted by a heteroaryl group wherein the heteroaryl group may be unsubstituted or may be substituted as defined infra or Rn is substituted heteroaryl as defined infra with the proviso that if R ⁇ is substituted heteroaryl at least one substituent is a strong electron withdrawing group located ortho ox para to the ether bond.
  • a 4-amino-lH-imidazo[4,5-c]quinolin-l-yl alcohol of Formula X is alkylated with a halide of Formula XI to provide a lH-imidazo[4,5- e]quinolin-4-amine of Formula XII which is a subgenus of Formula I.
  • the alcohol of Formula X is reacted with sodium hydride in a suitable solvent such as N,N- dimethylformamide to form an alkoxide.
  • the halide is then added to the reaction mixture.
  • reaction can be carried out at ambient temperature or with gentle heating ( ⁇ 50°C) if desired.
  • product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme II the hydroxy group of a lH-imidazo[4,5- c]quinolin-l-yl alcohol of Formula XIII is protected with a benzyl group.
  • the alcohol of Formula XIII is reacted with sodium hydride in a suitable solvent such as N,N- dimethylformamide to form an alkoxide.
  • the alkoxide is then alkylated with benzyl bromide to provide a compound of Formula XIV.
  • the reaction can be carried out at ambient temperature.
  • Many compounds of Formula XIII are known, see for example, Gerster, U.S. Patent 4,689,338; others can readily be prepared using known synthetic routes, see for example, Gerster et al., U.S. Patent No. 5,605,899 and Gerster, U.S. Patent No. 5,175,296.
  • step (2) of Reaction Scheme II a compound of Formula XIV is oxidized to provide a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula XV using a conventional oxidizing agent capable of forming N-oxides .
  • a solution of a compound of Formula XIV in a suitable solvent such as chloroform or dichloromethane is oxidized using 3-chloroperoxybenzoic acid at ambient temperature.
  • step (3) of Reaction Scheme II a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula XV is chlorinated to provide a 4-chloro-lH-imidazo[4,5-c]quinoline of Formula XVI.
  • a solution of a compound of Formula XV in a suitable solvent such as toluene is treated with phosphorous oxychloride at ambient temperature.
  • step (4) of Reaction Scheme II a 4-chloro-lH-imidazo[4,5-c]quinoline of Formula XVI is reacted with phenol to provide a 4-phenoxy-lH-imidazo[4,5-c]quinoline of Formula XVII.
  • the phenol is reacted with sodium hydride in a suitable solvent such as diglyme to form a phenoxide.
  • the phenoxide is then reacted at an elevated temperature with a compound of Formula XVI.
  • step (5) of Reaction Scheme II the benzyl protecting group is removed from a compound of Formula XVII to provide a 4-phenoxy-lH-imidazo[4,5-c]quinolin-l-yl alcohol of Formula XVIII.
  • the reaction is preferably carried out by adding triflic acid in a controlled fashion to a solution of a compound of Formula XVII in a suitable solvent such as dichloromethane at ambient temperature.
  • step (6) of Reaction Scheme II a 4-phenoxy-lH-imidazo[4,5-c]quinolin-l-yl alcohol of Formula XVIII is alkylated with halide ⁇ al-R ⁇ to provide a 4-phenoxy-lH- imidazo[4,5-c]quinolin-l-yl ether of Formula XIX.
  • Formula XVIII is formed by adding the alcohol to a biphasic mixture of aqueous 50% sodium hydroxide and an inert solvent such as dichloromethane in the presence of a phase transfer catalyst such as benzyltrimethlammonium chloride. The alkoxide is then alkylated. The reaction can be carried out at ambient temperature.
  • a 4-phenoxy-lH-imidazo[4,5-c]quinolin-l-yl ether of Formula XIX is aminated to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XII which is a subgenus of Formula I.
  • the reaction can be carried out by combining a compound of Formula XIX with ammonium acetate and heating the resulting mixture at ⁇ 150°C.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Tetrahydroimidazoquinolines of the invention can be prepared according to Reaction Scheme III where R, R 2 , Rn, X and n are as defined above.
  • a 4-amino-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l- yl alcohol of Formula XX is alkylated with a halide of Formula XI to provide a 6,7,8,9- tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine of Formula XXI which is a subgenus of Formula III.
  • the alcohol of Formula XX is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide.
  • the alkoxide is then combined with the halide.
  • the reaction can be carried out at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme IV a lH-imidazo[4,5-c]quinolin-l-yl alcohol of Formula XIII is alkylated with a halide of Formula XXII to provide a lH-imidazo[4,5- c]quinolin-l-yl ether of Formula XXIII.
  • Formula XXII are combined in a biphasic mixture of 50% aqueous sodium hydroxide and a suitable solvent such as dichloromethane in the presence of a phase transfer catalyst such as benzyltrimethylammonium chloride.
  • the reaction can be run at ambient temperature.
  • step (2) of Reaction Scheme IV a lH-imidazo[4,5-c]quinoline of Formula XXIII is oxidized using the method of step (2) of Reaction Scheme II to provide a 1H- imidazo[4,5-c]quinoline-5N-oxide of Formula XXIV.
  • step (3) of Reaction Scheme IV a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula XXIV is reacted with trichloroacetyl isocyanate to provide a lH-imidazo[4,5- c]quinolin-4-yl acetamide of Formula XXV.
  • the isocyanate is added in a controlled fashion at ambient temperature to a solution of the 5N-oxide in a suitable solvent such as dichloromethane.
  • step (4) of Reaction Scheme IV a lH-imidazo[4,5-c]quinolin-4-yl acetamide of Formula XXV is hydrolyzed to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XXVI.
  • the hydrolysis can be carried out by conventional methods preferably by treating a solution of a compound of Formula XXV in methanol with sodium methoxide.
  • step (5) of Reaction Scheme IV lH-imidazo[4,5-c]quinolin-4-amine of Formula
  • XXVI is coupled with a halide of formula ⁇ al-R] 2 using a transition metal catalyst to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XXVII which is a subgenus of Formula II.
  • a compound of Formula XXVI is combined with the halide in the presence of copper (I) iodide, dichlorobis(triphenylphosphine)palladium(II), and excess triethylamine in a suitable solvent such as N,N-dimethylformamide or acetonitrile.
  • the reaction is preferably carried out at an elevated temperature (60-80°C).
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Step (1) of Reaction Scheme V the amino group of a lH-imidazo[4,5-c]quinolin- 4-amine of Formula XXVI is protected with tert-butoxycarbonyl groups.
  • a compound of Formula XXVI is combined with di-tert-butyl dicarbonate in a suitable solvent such as N,N-dimethylformamide in the presence of 4-(dimethylamino)pyridine and triethylamine. The reaction is carried out at an elevated temperature (80-85°C).
  • a protected lH-imidazo[4,5-c]quinol_n-4-amine of Formula XXVIII is coupled with a halide of formula ⁇ al-R ⁇ 2 using a transition metal catalyst to provide a protected lH-imidazo[4,5-c]quinolin-4-amine of Formula XXIX.
  • a compound of Formula XXVIII is combined with the halide in the presence of copper (I) iodide, dichlorobis(triphenylphosphine)palladium(II), and excess triethylamine in a suitable solvent such as N,N-dimethylformamide or acetonitrile.
  • the reaction can be carried out at ambient temperature or at an elevated temperature (40-80°C).
  • step (3) of Reaction Scheme V the protecting groups are removed by hydrolysis under acidic conditions to provide a lH-imidazo[4,5-c]quinolin-4-amine of Fo ⁇ nula XXVII which is a subgenus of Formula II.
  • a compound of Formula XXIX is treated with trifluoroacetic acid in a suitable solvent such as dichloromethane.
  • the reaction can be run at ambient temperature or at a reduced temperature (0°C).
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (4) of Reaction Scheme V the alkyne bond of a protected lH-imidazo[4,5- e]quinolin-4-amine of Formula XXIX is reduced to provide a protected lH-imidazo[4,5- c]quinolin-4-amine of Formula XXX.
  • the reduction is carried out using a conventional heterogeneous hydrogentation catalyst such as platinum oxide, platinum on carbon or palladium on carbon.
  • the reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as methanol.
  • step (5) of Reaction Scheme V the protecting groups of a compound of Formula
  • XXX are removed in the same manner as in step (3) to provide a lH-imidazo[4,5- c]quinolin-4-amine of Formula XXXI which is a subgenus of Formula I.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme VI the amino group of a lH-imidazo[4,5- c]quinolin-4-amine of Formula XXVI is protected with benzyloxycarbonyl groups.
  • a compound of Formula XXVI is combined with dibenzyl dicarbonate in a suitable solvent such as N,N-dimethylformamide. The reaction can be carried out at ambient temperature or with mild heating (40°C).
  • a protected lH-imidazo[4,5-c]quinolin-4-amine of Formula XXXII is coupled with a halide of formula ⁇ al-R ⁇ 2 using a transition metal catalyst to provide a protected lH-imidazo[4,5-c]quinolin-4-amine of Formula XXXIII.
  • a compound of Formula XXXII is combined with the halide in the presence of copper (I) iodide, dichlorobis(triphenylphosphine)palladium(II), and excess triethylamine in a suitable solvent such as N,N-dimethylformamide or acetonitrile.
  • the reaction can be carried out at ambient temperature or at an elevated temperature (40-80°C).
  • step (3) of Reaction Scheme VI the protecting groups are removed by hydrolysis to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XXVII which is a subgenus of Formula II.
  • a compound of Formula XXXIII is treated with sodium methoxide in a suitable solvent such as methanol.
  • the reaction can be run at ambient temperature.
  • the product or a phannaceutically acceptable salt thereof can be isolated using conventional methods .
  • step (4) of Reaction Scheme VI the protecting groups of a compound of Formula XXXIII are removed by hydrogenolysis and the alkyne bond is reduced to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XXXI which is a subgenus of Formula I.
  • the hydrogenolysis/reduction is carried out using palladium hydroxide on carbon.
  • the reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as methanol.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme VII a 2,4-dichloro-3-nitroquinoline of Formula XXXIV is reacted with an amine of Formula R ⁇ -O-X-NH 2 to provide a 2-chloro-3- nitroquinolin-4-amine of Formula XXXV.
  • the reaction can be carried out by adding the amine to a solution of a compound of Formula XXXIV in a suitable solvent such as chloroform or dichloromethane and optionally heating.
  • a suitable solvent such as chloroform or dichloromethane
  • Many quinolines of Formula XXXIV are known or can be prepared using known synthetic methods (see for example, Andre et al., U.S. Patent No. 4,988,815 and references cited therein).
  • step (2) of Reaction Scheme VII a 2-chloro-3-nitroquinolin-4-amine of Formula
  • XXXV is reduced to provide a 2-chloroquinoline-3,4-diamine of Formula XXXVI.
  • the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon.
  • the reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as isopropyl alcohol or toluene.
  • XXXVI is is reacted with a carboxylic acid or an equivalent thereof to provide a 4-chloro- lH-imidazo[4,5-c]quinoline of Formula XXXVII.
  • Suitable equivalents to carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates.
  • the carboxylic acid or equivalent is selected such that it will provide the desired R 2 substituent in a compound of Formula XXXVII.
  • triethyl orthofonnate will provide a compound where R 2 is hydrogen and triethyl orthoacetate will provide a compound where R 2 is methyl.
  • the reaction can be run in the absence of solvent or in an inert solvent such as toluene.
  • the reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
  • a catalyst such as pyridine hydrochloride can be included.
  • step (3) can be carried out by (i) reacting the diamine of Formula XXXVI with an acyl halide of Formula R 2 C(O)Cl and then (ii) cyclizing.
  • the acyl halide is added to a solution of the diamine in an inert solvent such as acetonitrile, pyridine or dichloromethane.
  • the reaction can be carried out at ambient temperature.
  • the product of part (i) is heated in an alcoholic solvent in the presence of a base.
  • the product of part (i) is refluxed in ethanol in the presence of an excess of triethylamine or heated with methanolic ammonia.
  • step (ii) can be carried out by heating the reaction mixture after analysis indicates that step (i) is complete.
  • step (4) of Reaction Scheme VII a 4-chloro-lH-imidazo[4,5-c]quinoline of Formula XXXVII is aminated to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula I.
  • the reaction is carried out by heating (e.g.,125-175°C) a compound of Formula XXXVII under pressure in a sealed reactor in the presence of a solution of ammonia in an alkanol.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • a lH-imidazo[4,5-c]quinolin-4-amine of Formula XXXVIII is alkylated with a halide of Fonnula XXXIX to provide a lH-imidazo[4,5- c]quinolin-4-amine of Formula I.
  • the compound of Formula XXXVIII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide.
  • the halide is then added to the reaction mixture.
  • the reaction can be carried out at an elevated temperature ( ⁇ 100°C). Alkylation occurs at both the N 1 and the N 3 nitrogens; however, the desired 1- isomer can be readily separated from the 3-isomer using conventional techniques such as column chromatography and recrystallization.
  • a 4-nitrotetrazolo[l,5-a]quinolin-5-ol of Formula XL is chlorinated to provide a 5-chloro-4-nitrotetrazolo[l,5-a]quinoline of Formula XLI.
  • Conventional chlorinating agents can be used.
  • the reaction is carried out using phosphorus oxychloride in a suitable solvent such as N,N- dimethylformamide.
  • 4-Nitrotetrazolo[l,5-a]quinolin-5-ols of Formula XL are known or can be prepared using known synthetic methods (see for example, Gerster, et al., U.S. Patent No. 5,741,908 and references cited therein).
  • step (2) of Reaction Scheme IX a 5-chloro-4-nitrotetrazolo[l,5-a]quinoline of Formula XLI is reacted with an amine of Formula R ⁇ -O-X-NH 2 to provide a 4- nitrotetrazolo[l,5-a]quinolin-5-amine of Formula XLII.
  • the reaction can be carried out by adding the amine to a solution of a compound of Formula XLI in a suitable solvent such as dichloromethane in the presence of triethylamine.
  • step (3) of Reaction Scheme IX a 4-nitrotetrazolo[l,5-a]quinolin-5-amine of Formula XLII is reduced using the method of step (2) in Reaction Scheme VII to provide a tetrazolo[l,5-a]quinolm-4,5-diamine of Formula XLIII.
  • step (4 ) of Reaction Scheme IX a tetrazolo[l,5-a]quinolin-4,5-diamine of Formula XLIII is cyclized using the method of step (3) in Reaction Scheme VII to provide a 6H-imidazo[4,5-c]tetrazolo[l,5- ]quinoline of Formula XLIV.
  • step (5) of Reaction Scheme IX a 6H-imidazo[4,5-c]tetrazolo[l,5- ⁇ ]quinoline of
  • Step (5) involves (i) reacting a compound of Formula XLIV with triphenylphosphine and then (ii) hydrolyzing.
  • Part (i) can be carried out by combining a compound of Formula XLIV with triphenylphosphine in a suitable solvent such as 1,2-dichlorobenzene and heating.
  • Part (ii) involves hydrolysis of the product from part (i). The hydrolysis can be carried out by conventional methods such as heating in the presence of water or a lower alkanol optionally in the presence of a catalyst such as an alkali metal hydroxide or lower alkoxide.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Tetrahydroimidazoquinolines of the invention can be prepared according to
  • step (1) of Reaction Scheme X a 4-amino-6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinolin-l-yl alcohol of Formula XX is alkylated using the method of Reaction Scheme III with a halide of formula ⁇ al-(C ⁇ 2 ) ⁇ - ⁇ 0 -C ⁇ C ⁇ to provide a 6,7,8,9-tetrahydro-lH- imidazo[4,5-c]quinolin-4-amine of Formula XLV.
  • step (2) of Reaction Scheme X a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin- 4-amine of Formula XLV is coupled using the method of step (5) of Reaction Scheme IV with a halide of Formula Hal-R ⁇ 2 to provide a 6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinolin-4-amine of Formula XLIV which is a subgenus of Formula IN.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme XI a 2,4-dihydroxy-3-nitro-6,7,8,9- tetrayhydroquinoline of Formula XLVII is chlorinated to provide a 2,4-dichloro-3-nitro- 6,7,8,9-tetrayhydroquinoline of Formula XLVIII.
  • Conventional chlorinating agents can be used.
  • the reaction is carried out by combining a compound of Formula XLVII with phosphorous oxychloride and then heating (55-65°C).
  • Compounds of Formula XLVII are known or can be prepared using known synthetic methods (see for example Nikolaides et al,. U.S. Patent 5,352,784 and references cited therein).
  • step (2) of Reaction Scheme XI a 2,4-dichloro-3-nitro-6,7,8,9- tetrayhydroquinoline of Formula XLVIII is reacted with an amine of Formula Ri-O-X-
  • step (3) of Reaction Scheme XI a 2-chloro-3-nitro-6,7,8,9-tetrahydroquinolin-4- amine of Formula XLIX is reacted with phenol using the method of step (4) of Reaction Scheme II to provide a 2-phenoxy-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula L.
  • step (4) of Reaction Scheme XI a 2-phenoxy-3-nitro-6,7,8,9-tetrahydroquinolin-amine-amine of Formula L.
  • 4-amine of Formula L is reduced using the method of step (2) of Reaction Scheme VII to provide a 2-phenoxy-6,7,8,9-tetrahydroquinolin-3,4-diamine of Formula LI.
  • step (5) of Reaction Scheme XI a 2-phenoxy-6,7,8,9-tetrahydroquinolin-3,4- diamine of Formula LI is cyclized using the method of step (3) of Reaction Scheme VII to provide a 4-phenoxy-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinoline of Formula LU.
  • step (6) of Reaction Scheme XI a 4-phenoxy-6,7,8,9-tetrahydro-lH- imidazo[4,5-c]quinoline of Formula LII is aminated using the method of step (7) of Reaction Scheme II to provide a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine of Formula III.
  • the invention also provides novel compounds useful as intermediates in the synthesis of the compounds of Formulas (I), (II), (III), and (IV). These intermediate compounds have the structural Formulas (V) - (IX) and (XLIV) described in more detail below.
  • One class of intermediate compounds has Formula (V):
  • X is -CHR 3 -, -CHR 3 -alkyl-, or -CHR 3 -alkenyl-;
  • Ri is selected from the group consisting of: -heteroaryl; -heterocyclyl; -R ⁇ - heteroaryl;
  • R 2 is selected from the group consisting of: -hydrogen; -alkyl;
  • R t is alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R 3 is independently H or Ci-io alkyl;
  • Rio is heteroaryl or heterocyclyl; each Y is independently -O- or -S(O)o- 2 -; n is 0 to 4; and each R present is independently selected from the group consisting of Ci-io alkyl, Ci-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • X is -CHR 3 -, -CHR 3 -alkyl-, or -CHR 3 -alkenyl- Ri is selected from the group consisting of: -heteroaryl; -heterocyclyl; - t- heteroaryl; -R 4 -heterocyclyl; and
  • R 2 is selected from the group consisting of: -hydrogen; -alkyl; -alkenyl;
  • T is alkyl or alkenyl, which may be interrupted by one or more - - groups; each R 3 is independently H or Ci-io alkyl;
  • Rio is heteroaryl or heterocyclyl; each Y is independently -O- or -S(O)o- 2 -; n is 0 to 4; and each R present is independently selected from the group consisting of Ci-io alkyl, d-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • X is -CHR 3 -, -CHR 3 -alkyl-, or-CHR 3 -alkenyl-;
  • Ri is selected from the group consisting of: -heteroaryl;
  • R_ t is alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R 3 is independently H or C ⁇ - 10 alkyl; n is 0 to 4; and each R present is independently selected from the group consisting of C 1-10 alkyl, C ⁇ - 10 alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • Another class of intermediate compounds has the Formula (XLIV):
  • X is -CHR 3 -, -CHR 3 -alkyl-, or -CHR alkenyl-;
  • Ri is selected from the group consisting of: -heteroaryl; -heterocyclyl; -R 4 - heteroaryl; and -R -heterocyclyl;
  • R 2 is selected from the group consisting of: -hydrogen; -alkyl; -alkenyl; -aryl;
  • j is alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R 3 is independently H or Ci-io alkyl; each Y is independently -O- or -S(O)o- 2 -; n is 0 to 4; and each R present is independently selected from the group consisting of Ci-io alkyl, Ci-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • X is -CHR 3 -, -CHR 3 -alkyl-, or -CHR 3 -alkenyl-;
  • Ri is selected from the group consisting of: -heteroaryl; -heterocyclyl; -I - heteroaryl; and
  • R 2 is selected from the group consisting of: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl;
  • R t is alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R 3 is independently H or Ci-io alkyl; each Y is independently -O- or -S(O)o- 2 -; n is 0 to 4; each R present is independently selected from the group consisting of Ci-io alkyl, Ci-io alkoxy, hydroxy, halogen and trifluoromethyl; and
  • R 7 is tert-butyl or benzyl; or a pharmaceutically acceptable salt thereof.
  • a further class of intermediates are imidazoquinoline-4-chloro compounds of the Formula (IX)
  • X is -CHR 3 -, -CHR 3 -alkyl-, or -CHR 3 -alkenyl-;
  • Ri is selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • -alkyl- Y-aryl and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; -halogen; -N(R 3 ) 2 ; -CO-N(R 3 ) 2 ; -CO-Ci-io alkyl; -CO-O-Ci-io alkyl;
  • R-t is alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R 3 is independently H or Ci-io alkyl; each Y is independently -O- or -S(O)o- 2 -; n is 0 to 4; and each R present is independently selected from the group consisting of Ci-io alkyl, d-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • alkyl As used herein, the terms "alkyl”, “alkenyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms. Preferred groups have a total of up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and adamantyl.
  • alkyl and alkenyl portions of -X- groups can be unsubstituted or substituted by one or more substituents, which substituents are selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl.
  • substituents are selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl.
  • haloalkyl is inclusive of groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of groups that include the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
  • aryl as used herein includes carbocyclic aromatic rings or ring systems.
  • aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.
  • heteroaryl includes aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N).
  • Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, quinoxalinyl, benzimidazolyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, quinazolinyl, purinyl, and so on.
  • Heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N) and includes the fully saturated and partially unsaturated derivatives of any of the above mentioned heteroaryl groups.
  • exemplary heterocyclic groups include pyrrolidinyl, tetiahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, and the like.
  • the aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbon
  • preferred heteroaryl groups include 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrimidine, and 5-pyrimidine.
  • no R substituents are present (i.e., n is 0).
  • Prefened R groups include hydrogen, alkyl groups having 1 to 4 carbon atoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and cyclopropylmethyl), methoxyethyl, and ethoxymethyl.
  • these preferred substituents if present, can be present in the compounds of the invention in any combination.
  • the invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, and the like.
  • isomers e.g., diastereomers and enantiomers
  • salts e.g., sodium bicarbonate
  • solvates e.g., sodium bicarbonate
  • polymorphs e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium
  • compositions of the invention contain a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier.
  • a therapeutically effective amount means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction, antitumor activity, and/or antiviral activity.
  • compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg, of the compound to the subject.
  • Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
  • the compounds of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, etc.
  • the compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
  • Cytokines whose production may be induced by the administration of compounds according to the invention generally include interferon- ⁇ (IFN- ⁇ ) and/or tumor necrosis factor- (TNF- ⁇ ) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include IFN- ⁇ , TNF- ⁇ , IL-1, IL-6, IL-10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and tumors. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
  • Certain compounds of the invention have been found to preferentially induce the expression of IFN- ⁇ in a population of hematopoietic cells such as PBMCs (peripheral blood mononuclear cells) containing pDC2 cells (precursor dendritic cell-type 2) without concomitant production of significant levels of inflammatory cytokines.
  • PBMCs peripheral blood mononuclear cells
  • pDC2 cells precursor dendritic cell-type 2
  • the compounds of the invention affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction.
  • the compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes. Compounds of the invention also have an effect on the acquired immune response.
  • T helper type 1 (Thl) cytokine IFN- ⁇ is induced indirectly and the production of the T helper type 2 (Th2) cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.
  • Th2 T helper type 2
  • the compounds are expected to be useful in the treatment of atopic diseases, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
  • atopic diseases e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
  • the immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce the production of cytokines such as IFN- ⁇ and/or TNF- ⁇ , the compounds are particularly useful in the treatment of viral diseases and tumors.
  • This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to, viral diseases including genital warts; common warts; plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I and Type II; molluscum contagiosum; variola, particularly variola major; rhinovirus; adenovirus; influenza; para-influenza; HIV;
  • CMV CMV
  • VZV intraepithelial neoplasias such as cervical intraepithelial neoplasia; human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g.
  • Candida aspergillus, and cryptococcal meningitis
  • neoplastic diseases e.g., basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, rayelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers
  • parasitic diseases e.g., basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, rayelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers
  • parasitic diseases e.g.
  • Additional diseases or conditions that can be treated using the compounds of the invention include actinic keratosis; eczema; eosinophilia; essential thrombocythaemia; leprosy; multiple sclerosis; Ommen's syndrome; discoid lupus; Bowen's disease; Bowenoid papulosis; alopecia areata; the inhibition of keloid formation after surgery and other types of post-surgical scars.
  • the compounds could enhance or stimulate the healing of wounds, including chronic wounds.
  • the compounds may be useful for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients.
  • An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN- ⁇ , TNF- ⁇ , IL-1, IL-6, IL-10 and IL-12 that is increased over the background level of such cytokines.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • the invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
  • An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • the invention is further described by the following examples, which are provided for illustration only and are not intended to be limiting in any way.
  • N,N-(bis tert-butoxycarbonyl)- 1-[2-(2- propynyloxy)ethyl]-lH-imidazo[4,5-c]quinolin-4-amine 1.0 g, 2.14 mmol
  • triethylamine 0.8 mL, 5.56 mmol
  • N,N-dimethylformamide 25 mL
  • Example 1 Part G Using the general method of Example 1 Part G, the material from Part B was hydrolyzed to provide 0.11 g of l-(2- ⁇ [3-(l,3-thiazol-2-yl)-2-propynyl]oxy ⁇ ethyl)-lH- imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 157-159°C.
  • N,N-(Bis benzyloxycarbonyl)-l-[2-(2-propynyloxy)ethyl]-lH-imidazo[4,5- c]quinolin-4-amine (1.00 g, 1.87 mmol), anhydrous acetonitrile (10 mL), triethylamine (0.68 mL, 4.86 mmol), and 2-bromopyrimidine (0.327 g, 2.06 mmol) were combined. Under a nitrogen atmosphere copper (I) iodide (0.014 g) and dichlorobis(triphenylphosphine)palladium(II) (0.026 g) were added.
  • the reaction mixture was maintained at ambient temperature for 15 minutes and then heated to 80°C for 1.5 hours.
  • the reaction mixture was diluted with ethyl acetate and water.
  • the aqueous layer was separated and then extracted with ethyl acetate until no UV materials remained in the aqueous layer.
  • the organic fractions were combined, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure.
  • reaction mixture was allowed to stand over the weekend at which time analysis indicated the presence of some product with protected amine groups.
  • the reaction mixture was filtered to remove the catalyst and the filtrate was treated with sodium methoxide (1 mL of 25% in methanol) for about 16 hours to remove the protecting groups.
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was purified by column chromatography eluting with 1/1/1 ethyl acetate/methanol/hexane to provide 0.235 g of a solid. This material was stirred with hot toluene and then filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure.
  • N,N-(bis benzyloxycarbonyl)-l-[2- (2-propynyloxy)ethyl]-lH-imidazo[4,5-c]quinolin-4-amine (2.00 g, 3.74 mmol) was reacted with 4-bromopyridine (0.8 g, 4.12 mmol) to provide 1.47 g of a mixture of mono and di benzyloxycarbonyl protected l- ⁇ 2-[(3-pyridin-4-ylprop-2-ynyl)oxy]ethyl ⁇ -lH- imidazo[4,5-c]quinolin-4-amine.
  • Palladium hydroxide (0.57 g of 20% on carbon) was added to a solution of the material from Part A in methanol (-10 mL). The mixture was hydrogenated at 50 psi (3.5 Kg/cm 2 ) for 5 hours. More catalyst (0.07 g) was added and the hydrogenation was continued for another hour. The reaction mixture was filtered to remove catalyst and the filter cake was thoroughly washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 6/3/1 ethyl acetate/methanol/hexane and then triturated with diethyl ether to provide a solid.
  • N,N-(bisbenzyloxycarbonyl)-l-[2-(2- propynyloxy)ethyl]-lH-imidazo[4,5-c]quinolin-4-amine (2.5 g, 4.68 mmol)
  • anhydrous acetonitrile (20 mL)
  • triethylamine 1.7 mL, 12.2 mmol
  • 2-bromopyridine 0.5 mL, 5.14 mmol
  • Palladium hydroxide (0.776 g of 20% on carbon) was added to a solution of the material from Part A in methanol. The mixture was hydrogenated at 45 psi (3.2 Kg/cm 2 ) for 2.5 hours. The reaction mixture was filtered to remove catalyst and the filter cake was thoroughly washed with methanol. The filtrate was concentrated under reduced pressure to provide a glassy solid. This material was triturated with diethyl ether and hexane containing a small amount of toluene. The resulting powder was isolated by filtration and dried at 78°C overnight in a vacuum oven.
  • This material was further purified by column chromatography eluting with 9/1 dichloromethane/methanol with a few drops of ammonium hydroxide to provide 25 mg of l-[2-(3-pyridin-2-ylpropoxy)ethyl]-lH- imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 138-140°C.
  • N,N-(Bisbenzyloxycarbonyl)-l-[2-(2- propynyloxy)ethyl]-lH-imidazo[4,5-c]quinolin-4-amine (3.25 g, 6.08 mmol)
  • anhydrous N,N-dimethylformamide (15 mL)
  • triethylamine 2.2 mL, 15.8 mmol
  • 2- bromothiazole 0.6 mL, 6.69 mmol
  • Palladium hydroxide (-2 g of 20% on carbon) was added to a solution of the material from Part A in methanol. The mixture was hydrogenated at 45 psi (3.2 Kg/cm ) for 3 hours. More catalyst (0.3 g) was added twice and the hydrogenation was continued for a total of -25 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to provide 1.3 g of mono benzyloxycarbonyl protected l- ⁇ 2-[3-(l,3-thiazol-2-yl)propoxy]ethyl ⁇ -lH-imidazo[4,5- c]quinolin-4-amine.
  • N,N-(bis tert-butyoxycabonyl)-l-[2-(2- propynyloxy)ethyl]-lH-imidazo[4,5-c]quinoIin-4-amine (1.75 g, 3.75 mmol)
  • 3- iodopyridine (0.85 g, 4.13 mmol)
  • triethylamine 1.4 mL
  • acetonitrile 15 mL
  • Example 8 Part A Using the general method of Example 8 Part A, except that the reaction temperature was raised to 80°C, N,N-(bis tert-butyoxycabonyl)-l-[2-(2- propynyloxy)ethyl]-lH-imidazo[4,5-c]quinolin-4-amine (2.5 g, 5.36 mmol) was coupled with 5-bromopyrimidine (0.94 g, 5.89mmol) to provide 1.59 g of N,N-(bis tert- butoxycarbonyl)-! - ⁇ 2-[(3-pyrimidin-5-ylprop-2-ynyl)oxy]ethyl ⁇ -lH-imidazo[4,5- c] quinolin-4-amine .
  • a methanol solution of the material from Part A was combined with catalyst ( 5% platinum on carbon, palladium hydroxide and 10%> palladium on carbon were used in succession) and hydrogenated to provide 0.60 g of N,N-(bis tert-butoxycarbonyl)-l-[2-(3- pyrimidin-5 -ylpropoxy)ethyl] - 1 H-imidazo [4,5-c] quinolin-4-amine .
  • Example 8 Part C Using the general method of Example 8 Part C, the material from Part B was hydrolyzed to provide 0.14 g of l-[2-(3-pyrimidin-5-ylpropoxy)ethyl]-lH-imidazo[4,5- c]quinolin-4-amine, m.p. 159-161°C.
  • the reaction mixture was allowed to stir at ambient temperature overnight and then it was concentrated under reduced pressure to provide a dark oil.
  • the oil was purified by column chromatography eluting with 5% methanol in dichloromethane to provide a light yellow oil.
  • the oil was treated with 1.0 M hydrogen chloride to provide a pink solid. This solid was recrystallized twice from acetonitrile and the resulting product was dried in a vacuum oven at 80°C for 2 hours to provide 0.12 g of a mixture of the regio isomers of the desired product i.e.
  • the oil was purified by column chromatography eluting with 5% methanol in dichloromethane to provide a green crystalline solid. This material was recrystallized from isopropanol to provide 0.12 g of a mixture of the regio isomers of the desired product i.e.
  • reaction mixture was filtered through a layer of Celite® filter aid to remove the catalysts.
  • the filtrate was concentrated under reduced pressure to provide an oil.
  • This material was purified by flash chromatography (silica gel eluting with 3% methanol in dichloromethane) to provide 0.91 g of l-[2- (benzo[b]furan-2-ylmethoxy)ethyl]-lH-imidazo[4,5-c]quinoline as a yellow oil.
  • Part C 3-Chloroperoxybenzoic acid (0.65 g) was added in portions over a period of 5 minutes to a solution of the material from Part B in chloroform (15 mL). The progress of the reaction was monitored by TLC.
  • Phosphorous oxychloride (12.84 mL, 138 mmol) was slowly added to a mixture of l-[2-(benzyloxy)ethyl]-lH-imidazo[4,5-c]quinoline-5N-oxide (40.0 g, 125 mmol) and anhydrous toluene (600 mL). The reaction mixture was allowed to stir for about 30 minutes and then the volatiles were removed under reduced pressure. The resulting red oil was dissolved in dichloromethane, washed twice with saturated sodium bicarbonate, and then concentrated under reduced pressure. An attempt to recrystallize the residue from ethyl acetate resulted in a gum.
  • Phenol (6.21 g, 66 mmol) was added in portions to a chilled suspension of sodium hydride (2.79 g of 60% in mineral oil, 69.7 mmol) in diglyme (25 mL). When bubbling had subsided, a solution of the material from Part C in diglyme (10 mL) was added in a single portion. The resulting solution was heated to 110°C and stirred overnight. Analysis by TLC (3% methanol in dichloromethane) indicated that the reaction was complete. The solution was cooled to 0°C and a brown precipitate formed. The diglyme was decanted off. The solid was slurried with hexane and then isolated by filtration.
  • Example 14 Part B Using the general method of Example 14 Part B, the material from Part A was aminated to provide 0.39 g of l- ⁇ 2-[(3,5-dimethylisoxazol-4-yl)methoxy]ethyl ⁇ -lH- imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 213-215°C. Analysis: Calculated for C ⁇ 8 ⁇ 9 N 5 O 2 : %C, 64.08; %H, 5.68; %N, 20.76; Found: %C,
  • Example 17 1 -(2- ⁇ [3 -(Pyrimidin-2-yl)-2-propynyl] oxy ⁇ ethyl)- lH-imidazo[4,5-c]quinolin-4-amine trifluoroacetate
  • This tar was purified first by column chromatography (silica gel eluting with dichloromethane) and then by semi-preparative ⁇ PLC using Method A to provide 0.05 g of l-(2- ⁇ [3-(pyrimidin-2-yl)-2- propynyl]oxy ⁇ ethyl)-lH-imidazo[4,5-c]quinolin-4-amine trifluoroacetate as a spongy white solid, m.p. 214-215°C.
  • the reaction mixture was allowed to cool to ambient temperature and then it was diluted with dichloromethane. The resulting fine brown precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved into a minimum amount of N,N-dimethylformamide and put through a silica gel column. The appropriate fractions were combined and concentrated under reduced pressure. The residue was purified by semi-preparative ⁇ PLC using Method A to provide 0.1 g of l-(2- ⁇ [3-(fur-3-yl)-2-propynyl]oxy ⁇ ethyl)-lH- imidazo[4,5-c]quinolin-4-amine trifluoroacetate as a fluffy ivory solid, m.p. 160-162°C.
  • the 4-amino-lH-imidazo[4,5-c]quinolin-l-yl alcohol (25 mg) was placed in a 2 dram (7.4 mL) vial.
  • the vial was placed on a sonicator for about 15 to 30 minutes at ambient temperature to allow the alkoxide to form.
  • the halide (1.2 eq) was added and the vial was placed back on the sonicator for about 15 to 120 minutes at ambient temperature.
  • the reaction mixture was analyzed by LC/MS to confirm the formation of the desired product.
  • the reaction mixture was purified by semi-preparative
  • the semi-prep ⁇ PLC fractions were analyzed by LC-APCI/MS and the appropriate fractions were combined and lyophilized to provide the trifluoroacetate salt of the desired product, which was confirmed by accurate mass and 1H NMR spectioscopy.
  • the table below shows the structure of the free base, the theoretical mass (TM), and the measured mass (MM) or nominal mass (NM).
  • Part B A dried round bottom flask was charged with a stir bar, l-[2-(2- propynyloxy)ethyl]-lH-imidazo[4,5-c]quinoline-5N-oxide (57.5 g, 215.1 mmol), anhydrous toluene (200 mL) and anhydrous dimethyl formamide (400 mL) under a nitrogen atmosphere. Phosphorus oxychloride (23 mL, 247.4 mmol) was added dropwise over 20 minutes to this mixture leading to a modest exotherm ( ⁇ 40 °C). The reaction was judged complete after 1.25 hours at ambient temperature.
  • the solid was recrystallized from acetonitrile with a small amount of dimethyl formamide to provide 25 g of 4-phenoxy-l-[2-(prop-2-ynyloxy)ethyl]-lH-imidazo[4,5-c]qumoline as a crystalline solid.
  • the resulting oil was purified with chromatography over silica gel (95/5 dichloromethane/methanol), semi-preparative ⁇ PLC using method A, and recrystallization from ethyl acetate/hexane to provide 43 mg of l-[2-(3-thien-2-ylpropoxy)ethyl]-lH- imidazo[4,5-c]quinolin-4-amine as a white crystalline solid, m.p. 130.1 -131.6 °C.
  • Tetrazolo[l,5- ⁇ ]quinolin-5-ol (63.25 g, 0.34 mol) was added to glacial acetic acid
  • Triethyl orthoformate (21.1ml, 127mmol) was added to a solution of N 5 -[2-(3- pyridin-3-ylpropoxy)ethyl]tetrazolo[l,5- ]quinoline-4,5-diamine (30.8 g, 84.7 mmol) in
  • 1,2-dichloroethane 750 ml
  • the reaction was heated to reflux for 3 hours.
  • the reaction was cooled to room temperature and diluted with saturated sodium bicarbonate (200 ml).
  • Triphenylphosphine (27.0g, 115mmol) was added to a solution of 6-[2-(3-pyridin- 3-ylpropoxy)ethyl]-6H-imidazo[4,5-c]tetiazolo[l,5- ⁇ ]quinoline (28.7 g, 76.9 mmol) in
  • 1,2-dichlorobenzene (1 L). The reaction was heated at reflux temperature overnight. The dark red solution was cooled to room temperature and treated with IN ⁇ C1 (225 ml). A tan precipitate formed. The resulting mixture was concentrated in vacuo to yield a dark red/brown solid. This material was treated with 500 ml water and vigorously stirred. Excess triphenylphosphine and triphenylphosphine oxide formed as precipitates and were removed by vacuum filtration. The solid was washed with several portions of water followed by a final wash with dilute ⁇ C1 (1 :5, IN ⁇ Chwater).
  • the red/brown filtrate was collected, washed with ether (3 x 150ml), and treated with 10% NaO ⁇ solution until the p ⁇ reached 12.
  • the crude product formed as a tan precipitate and was collected by filtration.
  • Purification of the crude material was accomplished by treatment (2X) with activated charcoal (Darco-G60) in refluxing methanol. The charcoal was removed by filtration. The desired product formed as a precipitate during concentration of the filtrate.
  • N 5 -[2-(3-pyridin-3- ylpropoxy)ethyl]tetrazolo[l,5- ⁇ ]quinoline-4,5-diamine (0.70 g, 1.92 mmol) was dissolved in 1,2-dichloroethane (15 ml).
  • Triethyl orthoacetate (0.53 ml, 2.88 mmol) was added via syringe and the reaction was heated to reflux for 3 hours. Analysis by thin layer chromatography (95/5 chloroform/methanol) showed complete consumption of the diamine.
  • the reaction was quenched by the addition of water (15 ml). The phases were separated and the aqueous fraction was extracted with dichloromethane (3 10 ml).
  • N 5 - [2-(3 -pyridin-3 - ylpropoxy)ethyl]tetrazolo[l,5- ⁇ ]quinoline-4,5-diamine (2.48 g, 6.82 mmol) was dissolved in toluene (40 ml). Trimethyl orthovalerate (1.29 ml, 7.51 mmol) was added via syringe.
  • Example 35 Recrystallization from isopropyl alcohol gave 1.09 g of 2-butyl-l-[2-(3- pyridin-3-ylpropoxy)ethyl]-lH-imidazo[4,5-c]quinoline-4-amine as a beige solid.
  • N5-[2-(3-pyridin-3-ylpropoxy)ethyl]tetraazolo[l,5- a]quinoline-4,5-diamine (2.48 g, 6.82 mmol), 1,2-dichloroethane (30 ml), and triethylamine (1.14 ml, 8.2 mmol) were combined and the resulting solution was chilled in an ice water bath.
  • 3-methoxypropionyl chloride (0.92 g, 7.5 mmol) was added dropwise to the solution. The cooling bath was removed and the reaction was stirred for an additional 18 hours. The solution was quenched by the addition of water (30 ml).
  • the reaction was cooled to ambient temperature and then diluted with water (30 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 20 ml). The combined organic extracts were washed with brine (20 ml), dried (Na 2 SO 4 ), filtered and concentrated to yield an orange foam.
  • the stirred reaction mixture was heated to 60°C and maintained overnight. The reaction was quenched by pouring onto ice (1000 mL). The product oiled out of solution. The mixture was extracted with dichloromethane (4 xl 00 mL). The combined extracts were concentrated to dryness. The residue was taken up in 1:1 hexane/ethyl acetate (250 mL) and washed with water (2 x 50 mL). The organic layer was concentrated to dryness. The residue was found to contain excess phenol. The phenol was removed by taking the residue up in diethyl ether (500 mL) and stimng over 10% sodium hydroxide (250 mL) overnight. The layers were separated.
  • the reaction mixture was cooled and then taken up in IN ⁇ C1 (250 mL) and washed with diethyl ether (200 mL). The aqueous layer was then adjusted to p ⁇ l 1 with sodium hydroxide and extracted with dichloromethane (3 x 100 mL). The combined organics were concentrated to provide an orange syrup. The syrup was purified by column chromatography (10%> MeO ⁇ /C ⁇ 2C12). The appropriate fractions were combined and concentrated to provide a pale orange syrup. The syrup was found to be a mixture of the desired product and N-acetylated product. The mixture was treated with refluxmg IN HCl for 1 hour. The mixture was cooled, adjusted to pH 11 and then extracted with dichloromethane.
  • CYTOKINE INDUCTION IN HUMAN CELLS An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon and tumor necrosis factor ( ⁇ ) (IFN and TNF, respectively) secreted into culture media as described by Testerman et. al. In "Cytokine
  • PBMCs Peripheral blood mononuclear cells
  • Histopaque®-1077 The PBMCs are washed twice with Hank's Balanced Salts Solution and then are suspended at 3-4 x 10 6 cells/mL in RPMI complete.
  • the PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ) containing an equal volume of RPMI complete media containing test compound.
  • the compounds are solubilized in dimethyl sulfoxide (DMSO).
  • DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells Incubation
  • test compound is added at 60 ⁇ M to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells.
  • the PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (0.12 to 30 ⁇ M).
  • the final concentration of PBMC suspension is 1.5-2 X 10 6 cells/mL.
  • the plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere.
  • Interferon ( ⁇ ) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are expressed in pg/mL.
  • Tumor necrosis factor ( ⁇ ) (TNF)concentration is determined using ELISA kits available from Genzyme, Cambridge, MA; R&D Systems, Minneapolis, MN; or Pharmingen, San Diego, CA. Results are expressed in pg/mL.
  • the table below lists the lowest concentration found to induce interferon and the lowest concentration found to induce tumor necrosis factor for each compound. A "*" indicates that no induction was seen at any of the tested concentrations; generally the highest tested concentration was 10 or 30 ⁇ M.

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US6573273B1 (en) * 1999-06-10 2003-06-03 3M Innovative Properties Company Urea substituted imidazoquinolines
US6331539B1 (en) * 1999-06-10 2001-12-18 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
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US6756382B2 (en) 1999-06-10 2004-06-29 3M Innovative Properties Company Amide substituted imidazoquinolines
US6916925B1 (en) 1999-11-05 2005-07-12 3M Innovative Properties Co. Dye labeled imidazoquinoline compounds
JP3436512B2 (ja) * 1999-12-28 2003-08-11 株式会社デンソー アクセル装置
US6660747B2 (en) * 2000-12-08 2003-12-09 3M Innovative Properties Company Amido ether substituted imidazoquinolines
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US6525064B1 (en) 2000-12-08 2003-02-25 3M Innovative Properties Company Sulfonamido substituted imidazopyridines
US6664264B2 (en) * 2000-12-08 2003-12-16 3M Innovative Properties Company Thioether substituted imidazoquinolines
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US6545017B1 (en) 2000-12-08 2003-04-08 3M Innovative Properties Company Urea substituted imidazopyridines
US6667312B2 (en) 2000-12-08 2003-12-23 3M Innovative Properties Company Thioether substituted imidazoquinolines
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RU2308456C2 (ru) 2007-10-20
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US7049439B2 (en) 2006-05-23
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PL365995A1 (pl) 2005-01-24
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CA2436980C (en) 2011-03-29
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